The nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is generated as a t(2;5) chromosomal breakpoint product, typically in CD30(+) anaplastic large cell lymphomas. Activation of the NPM-ALK tyrosine kinase by NPM dimerisation causes autophosphorylation at multiple tyrosine residues and the consequent recruitment of a 'signalosome' that couples the fusion protein to pathways regulating mitogenesis and apoptosis. This review focuses on recent advances in our understanding of the transforming signals induced by this fusion protein in mouse models.